tbuckley/cabot-search huggingface dataset:
Immunomodulation and endothelial barrier protection mediate the association between oral imatinib and mortality in hospitalised COVID-19 patients
Authors: Justin de Brabander, Erik Duijvelaar, Job R. Schippers, Patrick J. Smeele, Hessel Peters-Sengers, Jan Willem Duitman, Jurjan Aman, Harm Jan Bogaard, Tom van der Poll, Lieuwe D.J. Bos
Journal: European Respiratory Journal (2022)

Background Imatinib reduced 90-day mortality in hospitalised coronavirus disease 2019 (COVID-19) patients in a recent clinical trial, but the biological effects that cause improved clinical outcomes are unknown. We aimed to determine the biological changes elicited by imatinib in patients with COVID-19 and what baseline biological profile moderates the effect of imatinib. Methods We undertook a secondary analysis of a randomised, double-blind, placebo-controlled trial of oral imatinib in hospitalised, hypoxaemic COVID-19 patients. Mediating effects of changes in plasma concentration of 25 plasma host response biomarkers on the association between randomisation group and 90-day mortality were studied by combining linear mixed effect modelling and joint modelling. Moderation of baseline biomarker concentrations was evaluated by Cox regression modelling. We identified subphenotypes using Ward's method clustering and evaluated moderation of these subphenotypes using the aforementioned method. Results 332 out of 385 participants had plasma samples available. Imatinib increased the concentration of surfactant protein D (SP-D), and decreased the concentration of interleukin-6, procalcitonin, angiopoietin (Ang)-2/Ang-1 ratio, E-selectin, tumour necrosis factor (TNF)-α, and TNF receptor I. The effect of imatinib on 90-day mortality was fully mediated by changes in these biomarkers. Cluster analysis revealed three host response subphenotypes. Mortality benefit of imatinib was only present in the subphenotype characterised by alveolar epithelial injury indicated by increased SP-D levels in the context of systemic inflammation and endothelial dysfunction (hazard ratio 0.30, 95% CI 0.10–0.92). Conclusions The effect of imatinib on mortality in hospitalised COVID-19 patients is mediated through modulation of innate immune responses and reversal of endothelial dysfunction, and possibly moderated by biological subphenotypes.
Reshaping the tumor microenvironment with oncolytic viruses, positive regulation of the immune synapse, and blockade of the immunosuppressive oncometabolic circuitry
Authors: Teresa T Nguyen, Dong Ho Shin, Sagar Sohoni, Sanjay K Singh, Yisel Rivera-Molina, Hong Jiang, Xuejun Fan, Joy Gumin, Frederick F Lang, Christopher Alvarez-Breckenridge, Filipa Godoy-Vitorino, Lisha Zhu, W Jim Zheng, Lijie Zhai, Erik Ladomersky, Kristen L Lauing, Marta M Alonso, Derek A Wainwright, Candelaria Gomez-Manzano, Juan Fueyo
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Oncolytic viruses are considered part of immunotherapy and have shown promise in preclinical experiments and clinical trials. Results from these studies have suggested that tumor microenvironment remodeling is required to achieve an effective response in solid tumors. Here, we assess the extent to which targeting specific mechanisms underlying the immunosuppressive tumor microenvironment optimizes viroimmunotherapy. Methods We used RNA-seq analyses to analyze the transcriptome, and validated the results using Q-PCR, flow cytometry, and immunofluorescence. Viral activity was analyzed by replication assays and viral titration. Kyn and Trp metabolite levels were quantified using liquid chromatography–mass spectrometry. Aryl hydrocarbon receptor (AhR) activation was analyzed by examination of promoter activity. Therapeutic efficacy was assessed by tumor histopathology and survival in syngeneic murine models of gliomas, including Indoleamine 2,3-dioxygenase (IDO)-/- mice. Flow cytometry was used for immunophenotyping and quantification of cell populations. Immune activation was examined in co-cultures of immune and cancer cells. T-cell depletion was used to identify the role played by specific cell populations. Rechallenge experiments were performed to identify the development of anti-tumor memory. Results Bulk RNA-seq analyses showed the activation of the immunosuppressive IDO-kynurenine-AhR circuitry in response to Delta-24-RGDOX infection of tumors. To overcome the effect of this pivotal pathway, we combined Delta-24-RGDOX with clinically relevant IDO inhibitors. The combination therapy increased the frequency of CD8 + T cells and decreased the rate of myeloid-derived suppressor cell and immunosupressive Treg tumor populations in animal models of solid tumors. Functional studies demonstrated that IDO-blockade-dependent activation of immune cells against tumor antigens could be reversed by the oncometabolite kynurenine. The concurrent targeting of the effectors and suppressors of the tumor immune landscape significantly prolonged the survival in animal models of orthotopic gliomas. Conclusions Our data identified for the first time the in vivo role of IDO-dependent immunosuppressive pathways in the resistance of solid tumors to oncolytic adenoviruses. Specifically, the IDO-Kyn-AhR activity was responsible for the resurface of local immunosuppression and resistance to therapy, which was ablated through IDO inhibition. Our data indicate that combined molecular and immune therapy may improve outcomes in human gliomas and other cancers treated with virotherapy.
Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of nonmelanoma skin cancer
Authors: Ann W Silk, Christopher A Barker, Shailender Bhatia, Kathryn B Bollin, Sunandana Chandra, Zeynep Eroglu, Brian R Gastman, Kari L Kendra, Harriet Kluger, Evan J Lipson, Kathleen Madden, David M Miller, Paul Nghiem, Anna C Pavlick, Igor Puzanov, Guilherme Rabinowits, Emily S Ruiz, Vernon K Sondak, Edward A Tavss, Michael T Tetzlaff, Isaac Brownell
Journal: Journal for ImmunoTherapy of Cancer (2022)

Nonmelanoma skin cancers (NMSCs) are some of the most commonly diagnosed malignancies. In general, early-stage NMSCs have favorable outcomes; however, a small subset of patients develop resistant, advanced, or metastatic disease, or aggressive subtypes that are more challenging to treat successfully. Recently, immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration (FDA) for the treatment of Merkel cell carcinoma (MCC), cutaneous squamous cell carcinoma (CSCC), and basal cell carcinoma (BCC). Although ICIs have demonstrated activity against NMSCs, the routine clinical use of these agents may be more challenging due to a number of factors including the lack of predictive biomarkers, the need to consider special patient populations, the management of toxicity, and the assessment of atypical responses. With the goal of improving patient care by providing expert guidance to the oncology community, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). The expert panel drew on the published literature as well as their own clinical experience to develop recommendations for healthcare professionals on important aspects of immunotherapeutic treatment for NMSCs, including staging, biomarker testing, patient selection, therapy selection, post-treatment response evaluation and surveillance, and patient quality of life (QOL) considerations, among others. The evidence- and consensus-based recommendations in this CPG are intended to provide guidance to cancer care professionals treating patients with NMSCs.
The Roughton–Forster equation for pulmonary diffusion: how it happened
Authors: Mike Hughes
Journal: European Respiratory Journal (2022)

<b>The Roughton–Forster equation of 1957 describes the transfer of oxygen and carbon monoxide from alveolar gas to pulmonary capillaries, as molecular diffusion across membranes and interstitium coupled to the reaction with haemoglobin in red cells</b> https://bit.ly/380cg0D
Chimeric antigen receptor T cells engineered to recognize the P329G-mutated Fc part of effector-silenced tumor antigen-targeting human IgG1 antibodies enable modular targeting of solid tumors
Authors: Sophia Stock, Mohamed-Reda Benmebarek, Anna-Kristina Kluever, Diana Darowski, Christian Jost, Kay-Gunnar Stubenrauch, Joerg Benz, Anne Freimoser-Grundschober, Ekkehard Moessner, Pablo Umana, Marion Subklewe, Stefan Endres, Christian Klein, Sebastian Kobold
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Chimeric antigen receptor (CAR) T cell therapy has proven its clinical utility in hematological malignancies. Optimization is still required for its application in solid tumors. Here, the lack of cancer-specific structures along with tumor heterogeneity represent a critical barrier to safety and efficacy. Modular CAR T cells indirectly binding the tumor antigen through CAR-adaptor molecules have the potential to reduce adverse events and to overcome antigen heterogeneity. We hypothesized that a platform utilizing unique traits of clinical grade antibodies for selective CAR targeting would come with significant advantages. Thus, we developed a P329G-directed CAR targeting the P329G mutation in the Fc part of tumor-targeting human antibodies containing P329G L234A/L235A (LALA) mutations for Fc silencing. Methods A single chain variable fragment-based second generation P329G-targeting CAR was retrovirally transduced into primary human T cells. These CAR T cells were combined with IgG1 antibodies carrying P329G LALA mutations in their Fc part targeting epidermal growth factor receptor (EGFR), mesothelin (MSLN) or HER2/neu. Mesothelioma, pancreatic and breast cancer cell lines expressing the respective antigens were used as target cell lines. Efficacy was evaluated in vitro and in vivo in xenograft mouse models. Results Unlike CD16-CAR T cells, which bind human IgG in a non-selective manner, P329G-targeting CAR T cells revealed specific effector functions only when combined with antibodies carrying P329G LALA mutations in their Fc part. P329G-targeting CAR T cells cannot be activated by an excess of human IgG. P329G-directed CAR T cells combined with a MSLN-targeting P329G-mutated antibody mediated pronounced in vitro and in vivo antitumor efficacy in mesothelioma and pancreatic cancer models. Combined with a HER2-targeting antibody, P329G-targeting CAR T cells showed substantial in vitro activation, proliferation, cytokine production and cytotoxicity against HER2-expressing breast cancer cell lines and induced complete tumor eradication in a breast cancer xenograft mouse model. The ability of the platform to target multiple antigens sequentially was shown in vitro and in vivo. Conclusions P329G-targeting CAR T cells combined with antigen-binding human IgG1 antibodies containing the P329G Fc mutation mediate pronounced in vitro and in vivo effector functions in different solid tumor models, warranting further clinical translation of this concept.
We need to understand why viral infections lead to acute asthma
Authors: Peter A.B. Wark
Journal: European Respiratory Journal (2022)

Acute exacerbations of asthma are an important and unmet asthma need [1], responsible for considerable morbidity and economic cost, across all age groups [2]. The most common triggers are acute viral infections and seasonal allergen exposure [1, 3]. This close epidemiological relationship is demonstrated by the fact that the prevalence of endemic rhinovirus is the commonest predictor of acute asthma in children, while in adults, the winter peak of asthma exacerbations remains strongly associated with influenza and other respiratory viruses [4]. Acute asthma is an important unmet clinical need, which needs to be better understood if new effective treatments are to be developed <https://bit.ly/3oM91ig>
Endoscopic sleeve gastroplasty for treatment of class 1 and 2 obesity (MERIT): a prospective, multicentre, randomised trial
Authors: Barham K Abu Dayyeh, Fateh Bazerbachi, Eric J Vargas, Reem Z Sharaiha, Christopher C Thompson, Bradley C Thaemert, Andre F Teixeira, Christopher G Chapman, Vivek Kumbhari, Michael B Ujiki, Jeanette Ahrens, Courtney Day, Manoel Galvao Neto, Natan Zundel, Erik B Wilson, Andres J Acosta, Dilhana Badurdeen, Navtej S Buttar, Matthew M Clark, Laura Eaton, Omar Ghanem, Karen Grothe, Pichamol Jirapinyo, Todd Kellogg, Connie L Klein, Manpreet Mundi, Andrew C Storm, Angielyn R Rivera, Todd D Wilson
Journal: The Lancet (2022)
Upadacitinib for the treatment of active non-radiographic axial spondyloarthritis (SELECT-AXIS 2): a randomised, double-blind, placebo-controlled, phase 3 trial
Authors: Atul Deodhar, Filip Van den Bosch, Denis Poddubnyy, Walter P Maksymowych, Désirée van der Heijde, Tae-Hwan Kim, Mitsumasa Kishimoto, Ricardo Blanco, Yuanyuan Duan, Yihan Li, Aileen L Pangan, Peter Wung, In-Ho Song
Journal: The Lancet (2022)
Cytisine Therapy Improved Smoking Cessation in the Randomized Screening and Multiple Intervention on Lung Epidemics Lung Cancer Screening Trial
Authors: Ugo Pastorino, Vito Ladisa, Sara Trussardo, Federica Sabia, Luigi Rolli, Camilla Valsecchi, Roberta E Ledda, Gianluca Milanese, Paola Suatoni, Mattia Boeri, Gabriella Sozzi, Alfonso Marchianò, Elena Munarini, Roberto Boffi, Silvano Gallus, Giovanni Apolone
Journal: Journal of Thoracic Oncology (2022)

Cytisine, a partial agonist-binding nicotine acetylcholine receptor, is a promising cessation intervention. We conducted a single-center, randomized, controlled trial (RCT) in Italy to assess the efficacy and tolerability of cytisine as a smoking cessation therapy among lung cancer screening participants.
Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial
Authors: Shun Lu, Lin Wu, Hong Jian, Ying Chen, Qiming Wang, Jian Fang, Ziping Wang, Yanping Hu, Meili Sun, Liang Han, Liyun Miao, Cuimin Ding, Jiuwei Cui, Baolan Li, Yueyin Pan, Xingya Li, Feng Ye, Anwen Liu, Ke Wang, Shundong Cang, Hui Zhou, Xing Sun, David Ferry, Yong Lin, Shuyan Wang, Wen Zhang, Chengli Zhang
Journal: The Lancet Oncology (2022)
Remote COVID-19 Assessment in Primary Care (RECAP) risk prediction tool: derivation and real-world validation studies
Authors: Ana Espinosa-Gonzalez, Denys Prociuk, Francesca Fiorentino, Christian Ramtale, Ella Mi, Emma Mi, Ben Glampson, Ana Luisa Neves, Cecilia Okusi, Laiba Husain, Jack Macartney, Martina Brown, Ben Browne, Caroline Warren, Rachna Chowla, Jonty Heaversedge, Trisha Greenhalgh, Simon de Lusignan, Erik Mayer, Brendan C Delaney
Journal: The Lancet Digital Health (2022)

Accurate assessment of COVID-19 severity in the community is essential for patient care and requires COVID-19-specific risk prediction scores adequately validated in a community setting. Following a qualitative phase to identify signs, symptoms, and risk factors, we aimed to develop and validate two COVID-19-specific risk prediction scores. Remote COVID-19 Assessment in Primary Care-General Practice score (RECAP-GP; without peripheral oxygen saturation [SpO
Clinical Outcomes and Immune Markers by Race in a Phase I/II Clinical Trial of Durvalumab Concomitant with Neoadjuvant Chemotherapy in Early-Stage TNBC
Authors: Julia Foldi, Adriana Kahn, Andrea Silber, Tao Qing, Emily Reisenbichler, Neal Fischbach, Justin Persico, Kerin Adelson, Anamika Katoch, Anees Chagpar, Tristen Park, Adam Blanchard, Kim Blenman, David L. Rimm, Lajos Pusztai
Journal: Clinical Cancer Research (2022)

Abstract Purpose: The incidence of triple-negative breast cancer (TNBC) is higher among Black or African American (AA) women, yet they are underrepresented in clinical trials. To evaluate safety and efficacy of durvalumab concurrent with neoadjuvant chemotherapy for stage I–III TNBC by race, we enrolled additional AA patients to a Phase I/II clinical trial. Patients and Methods: Our study population included 67 patients. The primary efficacy endpoint was pathologic complete response (pCR; ypT0/is, N0) rate. χ2 tests were used to evaluate associations between race and baseline characteristics. Cox proportional hazards models were used to assess association between race and overall survival (OS) and event-free survival (EFS). Multivariate logistic regression analyses were used to evaluate associations between race and pCR, immune-related adverse events (irAE) and recurrence. Results: Twenty-one patients (31%) self-identified as AA. No significant associations between race and baseline tumor stage (P = 0.40), PD-L1 status (0.92), and stromal tumor–infiltrating lymphocyte (sTIL) count (P = 0.57) were observed. pCR rates were similar between AA (43%) and non-AA patients (48%; P = 0.71). Three-year EFS rates were 78.3% and 71.4% in non-AA and AA patients, respectively [HR, 1.451; 95% confidence interval (CI), 0.524–4.017; P = 0.474]; 3-year OS was 87% and 81%, respectively (HR, 1.72; 95% CI, 0.481–6.136; P = 0.405). The incidence of irAEs was similar between AA and non-AA patients and no significant associations were found between irAEs and pathologic response. Conclusions: pCR rates, 3-year OS and EFS after neoadjuvant immunotherapy and chemotherapy were similar in AA and non-AA patients. Toxicities, including the frequency of irAEs, were also similar.
Highlights from Recent Cancer Literature
Journal: Cancer Research (2019)

Epigenetic Upregulation of TERTLee and colleagues analyzed the methylation landscape of the TERT promoter using bisulfite sequencing of normal tissue and TERT-expressing cancer cell lines.A 433-bp region within the TERT promoter containing 52 CpG sites (the TERT hypermethylated oncological region, THOR) was highly methylated in cancer cell lines compared with normal tissues.They observed a dramatic increase in THOR methylation in 1352 cancer tissues compared with 80 normal tissues.Higher THOR methylation correlated inversely with outcome.Skin and bone cancers with TERT promoter mutations and alternative lengthening of telomeres had low THOR methylation, consistent with convergent mechanisms of TERT upregulation.In luciferase experiments, methylation of this region increased TERT expression and treatment with decitabine reduced expression.Expert Commentary: This study advances our understanding of the mechanisms of replicative immortality in cancer.The dramatic increase in THOR methylation in cancer tissues makes this an attractive target for liquid biopsies aimed at early detection and/or surveillance across a range of malignancies.(Image courtesy of Wikimedia Commons.)
Editorial Board and Contents
Authors: Moran Furman, Paige Shaklee, Fred Kop, Patrick Scheffmann, Silvia Arber, Anders Björklund, J Paul Bolam, Sarah Bottjer, Rui Costa, Ann Marie, Craig Barry, J Dickson, Chris Doe, Craig Garner, Yukiko Goda, Kenneth Harris, Nancy Ip, Meyer Jackson, Maria Karayiorgou, Robert Malenka, Mark Mattson, Freda Miller, Richard Morris, Maiken Nedergaard, Eric Nestler, Anna Roe, Hitoshi Sakano, Greg Stuart, Marc Tessier-Lavigne, Chris Walsh
Journal: Trends in Neurosciences (2019)
Highlights of This Issue
Journal: Clinical Cancer Research (2019)

AKT kinase, as a component of the PI3K/mTOR/AKT cascade, mediates chemotherapy resistance in ovarian cancer. Following preclinical evidence that AKT inhibition restores chemotherapy efficacy, Blagden and colleagues conducted a Phase IB combination study of the AKT inhibitor afuresertib given with carboplatin and paclitaxel chemotherapy in 29 patients with platinum-resistant ovarian cancer. A 32% response rate was observed, and the combination showed acceptable tolerability. These findings support a future randomized evaluation of this combination in treatment-resistant ovarian cancer.CNS involvement worsens the prognosis of patients with T-cell acute lymphoblastic leukemia (T-ALL), because most anticancer drugs cannot pass the blood brain barrier. The histone demethylase LSD1 is considered to be a therapeutic target of T-ALL, in which LSD1 is overexpressed and acts as a founder abnormality. T-ALL cells, however, are resistant to tranylcypromine-based conventional LSD1 inhibitors. Saito and colleagues developed a novel LSD1 inhibitor, S2157, via N-alkylation of tranylcypromine and demonstrated its ability to eradicate CNS leukemia in a murine T-ALL model. The brain-permeable LSD1 inhibitor S2157 would be highly beneficial for T-ALL patients with CNS involvement.JX-594 (Pexa-vec) is one of the most promising oncolytic virus platforms in clinical development as one of the few oncolytic viruses in phase III clinical trials. Chon and colleagues show that a murine version of JX-594 (JX) remodels the tumor microenvironment by facilitating the accumulation of T cells. As a result, poorly immunogenic tumors become sensitive to cancer immunotherapy. Of note, the triple-combination therapy of JX, αPD-1, and αCTLA-4 maximizes anticancer immunity and induces durable regression with improved overall survival. These findings demonstrate the potential of JX in combination with immune checkpoint inhibitors for improving anticancer immune responses.Tumor-infiltrating NK cell (TI-NK) numbers were an independent predictor of pathological complete response, a surrogate marker of patient outcome, to anti-HER2 antibody-based treatment in primary HER2 positive breast cancer. The findings of Muntasell and colleagues add strong support for a role of antibody-dependent cellular cytotoxicity for the antitumor effects of anti-HER2 antibodies and, hence, for future research strategies to overcome resistance directed at the recruitment of NK cells in NK “cold” tumors. Furthermore, combination of HLA class I expression and TI-NK cell numbers improved the ability to predict long-term clinical outcomes, suggesting new ways to tailor anti-HER2 therapeutic strategies.
Editorial Board and Contents
Authors: Kusumika Mukherjee, Paige Shaklee, Fred Kop, Patrick Scheffmann, Michelle Arkin, Jacqueline Crawley, A Cuello, Laszlo Hunyady, Magnus Ingelman-Sundberg, Allan Kalueff, Terry Kenakin, Brian Kobilka, Michel Lazdunski, Christian Lüscher, Fiona Marshall, Jacopo Meldolesi, Wouter Moolenaar, Ruth Nussinov, Clive Page, Leonardo Pardo, Harald Sitte, Roger Summers, Rachel Tyndale, Ming-Wei Wang, Steven Watson, Stephen Waxman
Journal: Trends in Pharmacological Sciences (2019)
Folliculitis decalvans and dystrophic epidermolysis bullosa: a significant association
Authors: Bruno Matard, Emmanuelle Bourrat, Marine Cavalié, Christine Chiaverini, Pascal Reygagne
Journal: British Journal of Dermatology (2022)

Abstract This work reports 30 cases of folliculitis decalvans (FD) in patients with dystrophic epidermolysis bullosa (DEB) among a cohort of 125 DEB patients seen between 2010 and 2021 in 2 French expert centers for the management of inherited epidermolysis bullosa. Such an association between two rare diseases cannot be fortuitous and implies a physiopathological link that we discuss in this paper. This association is a new significant fact to add to the reflexion on FD causes, suggesting that skin abnormality of DEB could act as a factor of a specific skin barrier alteration which could favor FD. Scarring alopecia with tufted folliculitis and pustules on inflamed skin at the vertex of a woman with dominant dystrophic epidermolysis bullosa.